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Long-term stability of trastuzumab biosimilar under various storage conditions Posted 08/02/2019

Trastuzumab (TTZ) is a monoclonal antibody that interferes with the human epidermal growth factor receptor 2 (HER2). In some cancers, including certain types of breast cancers and gastric cancers, HER2 is overexpressed, causing cancer cells to reproduce uncontrollably. TTZ can be used in the management of these cancers.

While the stability of Herceptin reconstituted in vials or diluted in polyolefin bags for up to one month at 4°C has been demonstrated, no data are available for its biosimilars. In view of this, Vieillard et al. performed a study [1] to assess the long-term physical and chemical stability of CT-P6 using several complementary, previously validated methods in two contexts: reconstituted in vials at a concentration of 21 mg/mL, and after dilution in 0.9% NaCl polyolefin bags to bracket concentrations of 0.8 and 2.4 mg/mL for up to three months. Two storage temperatures were tested: 4°C and 22°C.

After 28 days of storage at 4°C and 22°C, no signs of physical instability were observed, including no formation of submicron, micron or particulate aggregates compared with the freshly prepared bags. Gel exclusion chromatography showed no oligomer formation or breakdown of the molecular structure of the compound. Moreover, ion chromatography revealed no significant change in the distribution of the ionic variants after 90 days storage at 4°C, indicating no chemical modification of the compound’s initial structure by hydrolysis (asparagine deamidation or isomerization). However, significant signs of hydrolysis were observed after 28 days storage at 22°C.

Second derivative UV and fluorescence-derived spectral analysis revealed no change to the tertiary structure of the antibody when stored at 4°C for 28 days. On the other hand, after storage at 22°C for 28 days, and 4°C for 90 days, small changes to the tertiary structure were observed. Nevertheless, identical thermal denaturation curves between batches and storage conditions indicate no strong destabilization of the three-dimensional structure even after 90 days storage at 22°C. Identical results were observed for the drug in vials after reconstitution. While the consequences of the modification of tertiary structure after 90 days storage at 4°C (possibly the cause of increased hydrodynamic diameter) on pharmacological activity are unclear, they are likely to be very limited because there were no signs of aggregation or chemical degradation.

These results have important use of CT-P6 in a hospital setting, the authors believe, justifying advanced preparation and implementation of dose-banding strategies. The authors suggest efficient responses to undesirable events, such as accidental breaks in the cold chain or the presence of a drug dilution that was prepared but not administered. These practices have the potential to improve patient management while reducing nurse and pharmacy workload, and will help to avoid unjustified losses of the drug. Furthermore, the authors believe the ability to dilute the drug could have important implications in the paediatric use of products which have been previously packaged for adults.

When considered alongside published data on rituximab and infliximab biosimilars, these results demonstrate that a TTZ biosimilar could have the same extensive stability as its originator, justifying its use under the same conditions.

The patent of the TTZ originator (Herceptin, Roche) expired in Europe in July 2014, and will expire in the US in June 2019. The European Commission approved Samsung Bioepis trastuzumab biosimilar, Ontruzant (SB3), in November 2017 [2], and Celltrion’s Herzuma (CT P6) in February 2018 [3]. In 2018, Amgen’s Kanjinti received EC approval, and the Committee for Medicinal Products for Human Use (CHMP) recommended that Pfizer’s Trazimera be approved for the treatment of breast and gastric cancer [4].

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Pharmacovigilance, traceability and building trust in biosimilar medicines

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1. Paul M, Astier A, Vieillard, V. Extended stability of a biosimilar of trastuzumab (CT-P6) after re-constitution in vials, dilution in polyolefin bags and storage at various temperatures. Generics and Biosimilars Initiative Journal (GaBI Journal). 2018;7(3):101-10. doi:10.5639/gabij.2018.0703.022
2. GaBI Online - Generics and Biosimilars Initiative. EC approval for trastuzumab biosimilar Ontruzant [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 3]. Available from: www.gabionline.net/Biosimilars/News/EC-approval-for-trastuzumab-biosimilar-Ontruzant
3. GaBI Online - Generics and Biosimilars Initiative. EC approval for trastuzumab biosimilar Herzuma [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 3]. Available from: www.gabionline.net/Biosimilars/News/EC-approval-for-trastuzumab-biosimilar-Herzuma
4. GaBI Online - Generics and Biosimilars Initiative. EMA approves adalimumab and trastuzumab biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 3]. Available from: www.gabionline.net/Biosimilars/News/EMA-approves-adalimumab-and-trastuzumab-biosimilars

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